Diabetic Retinopathy: Unraveling the Paradoxical Effects of Intensive Insulin Treatment

Background:Several major clinical trials have demonstrated that the tight glycemic control achieved with intensive insulin treatment may lead to an early worsening of diabetic retinopathy but that intensive long-term insulin treatment slows the progression of diabetic retinopathy.Objective:The goal of this article was to review developments in understanding both the pathophysiologic pathways involved in diabetic retinopathy and the biologic effects of insulin to provide a possible explanation why insulin treatment may have deleterious short-term effects yet provide long-term benefits.Methods:The content of this article was based on a search of MEDLINE from 1984 through 2006. English-language articles were chosen using the search terms diabetic retinopathy, insulin effects, and clinical trials.Results: Early worsening of diabetic retinopathy from acute intensive insulin treatment may result from upregulation of retinal vascular endothelial growth factor (VEGF) expression through increased binding of hypoxia-inducible factorla to the VEGF promoter. This results in increased gene transcription and VEGF levels. Increased VEGF levels also promote activation of protein kinase C; both events contribute to increased vasopermeability and a breakdown of the blood-retinal barrier. However, long-term insulin treatment reduces inflammatory and oxidative stress components that may contribute to progressive diabetic retinopathy. Both inflammatory effects and oxidative stress may play a role in the etiology of diabetic retinopathy. The beneficial biologic effects of insulin may thus supercede the acute deleterious effects of the VEGF-mediated blood-retinal-barrier breakdown. We speculate that the long-term beneficial effects of intensive insulin therapy on the progression of diabetic retinopathy arise from insulin's recently realized potent anti-inflammatory effects and ability to modulate redox-sensitive signaling pathways.Conclusions:Insulin treatment introduced before irreversible pathologic changes develop in the retina can impart beneficial effects to the vascular cells, may help suppress future deleterious events, and may slow the development or progression of retinal microangiopathic changes.